Quinazolinone derivative

ABSTRACT

An optically active form of the quinazolinone derivatives represented by the general formula (1): 
                         
[wherein Y represents a phenyl group or C2-C7 alkyl group; E represents —CH═ or nitrogen atom; and R represents a C1-C4 alkyl group and so on], or pharmaceutically acceptable salts thereof, has a selective antagonism for the M3 muscarinic receptor and depressant action on the frequency of rhythmic bladder contractions, and it is useful for the treatment of pollakiuria and urinary incontinence.

TECHNICAL FIELD

The present invention relates to optically active3,4,-dihydro-2(1H)-quinazolinone derivatives, production method thereof,medicaments containing them and their use for medicaments, especially,remedy for pollakiuria and urinary incontinence.

BACKGROUND ART

Oxybutinin is used as a medicament having an antagonistic action onmuscarinic receptors for the treatment of pollakiuria and urinaryincontinence, while the medicament is known to be inevitably associatedwith side effects due to its antagonistic action on muscarinicreceptors.

There are at least three known subtypes of muscarinic receptors whichare the sites of action of anticholinergic drugs, and it has been shownthat the M1 receptor is mainly localized in the brain, the M2 receptorin the heart, and the M3 receptor in smooth muscle and the glandulartissue, respectively. Accordingly, when a compound having anantagonistic action on muscarinic receptors is used as a remedy for thetreatment of pollakiuria and urinary incontinence, it is consideredpreferable that the selectivity for the M3 receptor is higher than thatfor the M1 and M2 receptors, and compounds with a variety of chemicalstructures, that is selective for the M3 receptor, have been reported.

However, dry mouth and mydriasis which are generally-known side effectsof anticholinergic drugs result from the antagonistic action on theM3-receptor, and thus it is difficult to eliminate these side effectsmerely by enhancing the selectivity for the M3 receptor. On the otherhand, research and development of non-cholinergic remedies for thetreatment of pollakiuria and urinary incontinence, such as α-receptorregulator, potassium channel opener and central muscular relaxtationaction, are proceeding, but no medicament having a satisfactory effecthas been obtained.

Accordingly, it is desired to obtain a compound that has another usefulaction for the treatment of pollakiuria and urinary incontinence inaddition to the antagonistic action on the muscarinic receptor as thecompound which can be widely used for the treatment of pollakiuria andurinary incontinence and which can reduce the side effects ofanticholinergic medicaments, due to having a plurality of actions.

On the other hand, quinazolinone derivatives have been reported as thecompound having a selective antagonism for the M3 muscarinic receptor inWO 00/23436.

DISCLOSURE OF INVENTION

An object of the present invention is to provide a compound havinganother useful action for the treatment of pollakiuria and urinaryincontinence in addition to the selective antagonism for the M3muscarinic receptor as the compound which can be widely used for thetreatment of pollakiuria and urinary incontinence and which may reducethe side effects of anticholinergic medicaments.

The present inventors have made an earnest study to solve the aboveproblem and have now found that an optically active form of thequinazolinone derivatives represented by the following general formula(1) or pharmaceutically acceptable salts thereof (hereinafterabbreviated as the compounds of the present invention as appropriate)not only has the selective antagonism for the M3 muscarinic receptor butalso newly has a depressant action on the frequency of rhythmic bladdercontractions, completing the present invention.

Furthermore, the compounds of the present invention have been found tohave a depressant action on afferent nerve activation. This action isconsidered to be useful for the treatment of pollakiuria and urinaryincontinence.

The present invention relates to the followings:

-   [1] An optically active form of the quinazolinone derivatives    represented by the general formula (1):

-   [wherein Y represents a phenyl group or C2-C7 alkyl group; E    represents a group of the formula —CH═ or nitrogen atom; and R    represents a fluorine atom, C1-C4 alkyl group, C1-C4 alkoxy group,    trifluoromethoxy group or 2,2,2-trifluoroethoxy group],-   or pharmaceutically acceptable salt thereof.-   [2] The optically active form of the quinazolinone derivatives    described in [1], which is (+) form, or pharmaceutically acceptable    salt thereof.-   [3] The optically active form of the quinazolinone derivatives    described in [1] or [2], wherein Y is a phenyl group and E is a    group of the formula —CH═, or pharmaceutically acceptable salt    thereof.-   [4] The optically active form of the quinazolinone derivatives    described in [1] or [2], wherein Y is a C2-C7 alkyl group and E is a    nitrogen atom, or pharmaceutically acceptable salt thereof.-   [5] The optically active form of the quinazolinone derivatives    described in any of [1] to [4], wherein Y is a C3-C7 alkyl group, or    pharmaceutically acceptable salt thereof.-   [6]    (+)-3-{1-[3-(2,2,2-trifluoroethoxy)benzyl]piperidin-4-yl}-4-phenyl-3,    4-dihydro-2(1H)-quinazolinone or pharmaceutically acceptable salt    thereof.-   [7]    (+)-3-[1-(3-trifluoromethoxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone    or pharmaceutically acceptable salt thereof.-   [8]    (+)-4-isopropyl-3-{1-[(6-methyl-2-pyridinyl)methyl]piperidin-4-yl}-3,    4-dihydro-2(1H)-quinazolinone or pharmaceutically acceptable salt    thereof.-   [9]    (+)-3-[1-(3-trifluoromethoxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone    fumarate.-   [10] A medicament comprising the compound described in any of [1] to    [9] or pharmaceutically acceptable salt thereof.-   [11] A remedy for treating pollakiuria or urinary incontinence    comprising the compound described in any of [1] to [9] or    pharmaceutically acceptable salt thereof as an active ingredient.

Various groups concerning the present invention are explained in detailbelow.

The C2-C7 alkyl group can be straight chain or branched and typicalexamples include ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl and 4-heptyl.

The C1-C4 alkyl group and the alkyl part in the C1-C4 alkoxy group canbe straight chain or branched and typical examples include methyl,ethyl, propyl, butyl and isopropyl.

The compounds of the present invention include adducts with solvent, forexample, hydrate and alcohol adducts (e.g. ethanolate).

The quinazolinone derivatives or pharmaceutically acceptable saltsthereof of the present invention can be produced by the methods below.

[wherein Y, E and R have the same meanings above and G represents aleaving group]

The optically active form (3) can be isolated from the racemic compoundgiven by the general formula (2) by optical resolution or separationwith high pressure liquid chromatography having a column for separatingoptical isomers. The optical resolution can be carried out byconventional method using an optically active acid as an opticalresolving reagent and sometimes by preferential crystallization. In casethat Y is a phenyl group, preferable optical resolving reagent for (+)form is N-benzoyl-D-phenylalanine.

Then, the optically active compound (1a) can be obtained by making thecompound (3) react with the aldehyde derivative (4) or the compound (5)according to known methods. The reaction with the aldehyde derivative(4) is a reductive alkylation and can be carried out by treating thecompound (3) and 1 to 5 equivalents of the aldehyde derivative (4) with1 to 5 equivalents of a reducing agent at 0-50° C. in a solvent. It ispreferably carried out by using sodium borohydride (NaBH₄), sodiumcyanoborohydride (NaBH₃CN) or sodium triacetoxyborohydride(NaB(OCOCH₃)₃H) as a reducing agent. Any solvent that does not interferethe reaction can be used and the reaction is preferably carried out byusing alcohol solvents such as methanol and ethanol, or halogenatedsolvents such as dichloromethane and 1,2-dichloroethane.

The alkylation reaction can be carried out by making the compound (3)react with the alkylation agent given by the general formula (5) in asolvent. The reaction is usually carried out in a solvent at 0-100° C.,preferably at room temperature to 70° C., in the presence of a base ifnecessary. Examples of the solvent include ether solvents such astetrahydrofuran and dioxane; aromatic hydrocarbon solvents such asbenzene and toluene; ketone solvents such as acetone and 2-butanone; anddimethylformamide. Examples of the base include sodium hydride,potassium carbonate, sodium carbonate and triethylamine. When potassiumcarbonate or sodium carbonate is used, an addition of sodium iodide orpotassium iodide may increase yield. Examples of the leaving group givenby G include halogen atoms such as chlorine, bromine and iodine;aromatic sulfonyloxy group such as benzenesulfonyloxy group andp-toluenesulfonyloxy group; and methanesulfonyloxy group.

Further, the optically active compound (1a) can also be produced by themethod below.

[wherein Y, E and R have the same meanings above]

The racemate (6) can be produced from the racemate (2) by the sameconversion as one from the compound (3) to the compound (1a) and thenthe optically active compound (1a) can be isolated from the racemate (6)by an optical resolution or separation by high pressure liquidchromatography with a column for separating optical isomers. The opticalresolution can be carried out by a conventional method using anoptically active acid as an optical resolving reagent and may be carriedout by preferential crystallization.

In the present invention, pharmaceutically acceptable salts are, forexample, salts with inorganic acids or organic acids. Examples of theinorganic acid include hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid and phosphoric acid; and examples of the organic acidinclude formic acid, acetic acid, propionic acid, lactic acid, tartaricacid, oxalic acid, fumaric acid, maleic acid, citric acid, malonic acid,methanesulfonic acid and benzenesulfonic acid. These salts are preparedby conventional methods, for example, by mixing with the above-mentionedacid in a solvent (e.g. water, methanol, ethanol, acetone).

The racemic compounds (1) and (2) are prepared according to the methodsdescribed in JP 7-215943A, and the compound (2) is also prepared by thefollowing method.

[wherein Y¹ and Y² independently represent a methyl, ethyl, propyl orisopropyl group, and X represents a chlorine atom or bromine atom]

The compound (9) is obtained by condensing the ketone derivative givenby the formula (7) with the amine derivative (8) in the presence oftitanium tetrachloride. In the reaction, 1 to 3 equivalents of the aminederivative (8) and 1 to 2 equivalents of the titanium tetrachloride, andif necessary 1 to 5 equivalents of a base such as triethylamine, areused based on 1 mol of the ketone compound given by the general formula(7), and the mixture is stirred at 0° C. to room temperature. Preferablesolvents are ethers such as tetrahydrofuran. Then, the obtained compound(9) was reduced to give the compound (10). By using sodium borohydride(NaBH₄), sodium cyanoborohydride (NaBH₃CN) or sodiumtriacetoxyborohydride (NaB(OCOCH₃)₃H) as a reducing agent, the reductionis well carried out. Any solvent that does not interfere the reactioncan be used and the reaction is preferably carried out by using alcoholsolvents such as methanol and ethanol, halogenated solvents such asdichloromethane and 1,2-dichloroethane or ether solvents such astetrahydrofuran. The compound (11) can be produced by heating thecompound (10) in the presence of potassium carbonate or sodium carbonateat 50 to 100° C. usually in a solvent. The conversion from the compound(11) to the compound (12) can be carried out according to thedescription of JP 7-215943A.

When the compounds of the present invention are used as a medicament,these may be administered orally or parenterally. That is, these may beorally administered in dosage forms that are conventionally used, suchas powders, granules, tablets, capsules, syrups and suspensions, or apreparation of their solution, emulsion or suspension may beparenterally administered in injection forms. Rectal administration mayalso be done in a suppository form. The above dosage forms suitable foradministration may be prepared by formulating the compounds of thepresent invention with, for example, acceptable conventional carriers,excipients, binders, stabilizers and diluents. When the compounds areused in an injection form, for example, acceptable buffers, solubilizingagents and isotonizing agents may also be added. The dose level andfrequency may be varied depending upon, for example, the disease to betreated, the symptom, the age, the body weight and the dosage form, andmay be from 0.1 to 2000 mg per day as the total daily dose for an adult,preferably from 1 to 200 mg, once or several times a day (e.g. 2 to 4times a day).

EXAMPLES

Hereinafter, the present invention is explained by reference examples,examples and test example in more detail; however the present inventiondoes not restricted by them.

Example 1 Production of(+)-3-{1-[3-(trifluoromethoxy)benzyl]piperidin-4-yl}-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

a) Production of(+)-3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

In 600 ml of 2-propanol, 10.0 g (32.5 mmol) of racemic3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone weredissolved under heating. At about 60° C., 8.76 g (32.5 mmol) ofN-benzoyl-D-phenylalanine were added thereto and refluxed under heating.After allowing to stand to cool, the precipitated crystals were filteredto give 11.9 g of N-benzoyl-D-phenylalanine salt of3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone.

The obtained salt was recrystallized from a mixed solvent of 120 ml ofmethanol and 1150 ml of 2-propanol to give 9.7 g of the recovered salt,which was followed by further recrystallization from 100 ml of methanoland 900 ml of 2-propanol to give 7.88 g of the salt.

The salt obtained above was separated between 120 ml of chloroform and120 ml of 0.5N—NaOH aqueous solution, and the chloroform layer waswashed with 0.5N—NaOH aqueous solution, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The concentratedresidue was subjected to recrystallization from 320 ml of acetonitrileto give 3.3 g of the above-titled compound.

[α]_(D) ²⁵+250.2° (c=1, methanol)

b) Production of(+)-3-[1-(3-trifluoromethoxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

Into a solution of 36.0 g (117 mmol) of(+)-3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 24.5g (190 mmol) of 3-trifluoromethoxybenzaldehyde in 500 ml ofdichloromethane, 54.6 g (129 mmol) of sodium triacetoxyborohydride wereadded at room temperature and stirred for 16 hours. Five hundredmilliliters (500 ml) of water, 100 ml of conc. aqueous ammonia and 500ml of chloroform were added thereto, and stirred. The separated oillayer was washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The concentratedresidue was purified by silica gel chromatography (hexane/ethyl acetate5/1) to give 51.7 g (114 mmol) of the above-titled compound.

Into a solution of 4.00 g of the above-titled compound in 47 ml of2-propanol, 1.44 g of fumaric acid were added and heated under stirring.After confirming that the crystals were dissolved, 47 ml of heptane wereadded thereto and cooled. The precipitated crystals were filtered togive 4.73 g of a 2:3 salt of the above-titled compound and fumaric acid.

mp: 196-197° C. [α]_(D) ²⁵+126.4° (c=1, methanol) Elemental analysis:Calculated values C, 60.45; H, 4.92; F, 8.69; N, 6.41. Experimentalvalues C, 60.37; H, 5.08; F, 8.63; N, 6.40 for C₆₆H₆₄F₆N₆O₁₆.

After 0.38 ml of 1N hydrochloric acid/ether solution was added into anisopropanol solution containing 150 mg of the above-titled compound andstirred, the mixture was concentrated under reduced pressure. Isopropylether was added to the concentrated residue and stirred. Theprecipitated crystals were filtered to give 130 mg of the above-titledcompound hydrochloride.

mp: 195-198° C.

By the similar procedures to Example 1b), the compounds below wereproduced from(+)-3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone.

Example 2-1 Optically Active Form of3-[1-(3-propylphenylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

¹H-NMR δ (CDCl₃): 0.92 (3H, t, J=7.3 Hz), 2.55 (2H, t, J=7.7 Hz), 3.44(2H, s), 4.38-4.45 (1H, m), 5.57 (1H, s), 6.75 (1H, d, J=7.7 Hz),7.38-7.41 (2H, m), 8.39 (1H, brs)

Example 2-2 Optically Active Form of3-[1-(3-propoxyphenylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

¹H-NMR δ (CDCl₃): 1.03 (3H, t, J=7.4 Hz), 3.43 (2H, s), 5.56 (1H, s),6.75-6.94 (5H, m), 7.07-7.28 (6H, m), 8.45 (1H, s)

Example 2-3 Optically Active Form of3-[1-(3-isopropoxyphenylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

¹H-NMR δ (CDCl₃): 1.32 (6h, dd, J=6.0 Hz, 2.1 Hz), 3.42 (2H, s), 5.56(1H, s), 6.75-6.90 (5H, m), 8.57 (1H, s)

Example 2-4 Optically Active Form of3-{1-[3-(2,2,2-trifluoroethoxy)phenylmethyl]piperidin-4-yl}-4-phenyl-3,4-dihydro-2(1H)-quinazolinone

¹H-NMR δ (CDCl₃): 3.43 (2H, s), 4.31 (2H, q, J=8.2 Hz), 5.57 (1H, s),6.78-6.96 (5H, m), 8.89 (1H, s)

Example 3 Production of(+)-4-isopropyl-3-{1-[(6-methyl-2-pyridinyl)methyl]piperidin-4-yl}-3,4-dihydro-2(1H)-quinazolinone

Into a solution of 150 mg (0.548 mmol) of4-isopropyl-3-(piperidin-4-yl)-3,4-dihydro-2(1H)-quinazolinone in 6 mlof dichloromethane, 135 mg (1.10 mmol) of 6-methylpyridin-2-carbaldehydewere added and stirred at room temperature for one hour. Three hundredand fifty milligrams (350 mg, 1.65 mmol) of sodium triacetoxyborohydridewere added thereto, and further stirred for 2 hours. After the reactionmixture was diluted with 10 ml of dichloromethane, 20 ml of 5% aqueoussodium hydroxide solution were added. The separated aqueous layer wasextracted with dichloromethane, and the combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The concentrated residue was purified by silica gelchromatography to give 170 mg (0.44 mmol) of a racemate of theabove-titled compound.

¹H-NMR δ (CDCl₃): 0.73 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=7.0 Hz), 2.55(3H, s), 3.64 (2H, s), 4.11 (1H, m), 6.66 (1H, d, J=7.7 Hz), 7.02 (1H,d, J=7.5 Hz), 7.54 (1H, t, J=7.6 Hz)

By separation of high pressure liquid chromatography with opticallyactive column under the following condition, the prior eluent wasseparated from 170 mg of the above racemate and purified to give 51 mgof the above-titled compound.

Column: about 25 cm of length, about 20 mm of internal diameter,stainless tube packed with aminopropyl silica gel having about 5 μm ofparticle diameter chemically bonded withN-[(R)-1-(α-naphthyl)ethylaminocarbonyl]-L-tert-leucine having about 5μm of particle diameter (commercial name SUMICHIRAL OA-4700 (SumikaChemical Analysis Service))

Mobile phase: hexane/chloroform/methanol=92/6/2

Flow rate: 20 ml/min

Detected wave length: 254 nm

Recrystallization of 50 mg of the above-titled compound from 0.5 ml ofacetonitrile gave 40 mg of columnar crystals.

mp: 144-145° C. [α]_(D) ²⁵+51.3° (c=1, methanol) Hydrochloride:

mp: 160-162° C. (decomposition)

Reference Example 1 Preparation of1-benzyl-4-{[2-methyl-1-(2-trichloroacetylaminophenyl)]-1-propenylamino}piperidine

Into a solution of 11.0 g (35.6 mmol) of isopropyl2-trichloroacetylaminophenyl ketone, 24.8 ml (178 mmol) of triethylamineand 10.2 g (53.5 mmol) of 4-amino-1-benzylpiperidine in 280 ml oftetrahydrofuran, 7.44 g (39.2 mmol) of titanium tetrachloride were addeddropwise under ice-cooling and stirred at room temperature for 24 hours.Aqueous 5% sodium bicarbonate solution and ethyl acetate were added andstirred. The separated oil layer was washed with saturated brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The concentrated residue was purified by silica gel chromatography(hexane/ethyl acetate/triethylamine 15/1/1) to give 6.74 g (14.0 mmol)of the above-titled compound.

¹H-NMR δ (CDCl₃): 1.25-1.51 (2H, m), 1.58 (3H, s), 1.62 (1H, m), 1.77(3H, s), 3.43 (2H, s), 8.29 (1H, d, J=7.9 Hz)

Reference Example 2 Preparation of1-benzyl-4-[2-methyl-1-(2-trichloroacetylaminophenyl)propenylamino]piperidine

Into a solution of 6.74 g (14.0 mmol) of1-benzyl-4-{[2-methyl-1-(2-trichloroacetylaminophenyl)]-1-propenylamino}piperidinein 100 ml of tetrahydrofuran, 8.81 g (140 mmol) of sodiumcyanoborohydride and 4.01 ml (70.0 mmol) of acetic acid were added andstirred at room temperature for 28 hours. Aqueous 5% sodium bicarbonatesolution and ethyl acetate were added and stirred. The separated oillayer was washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The concentratedresidue was purified by silica gel chromatography (hexane/ethylacetate/triethylamine 50/50/4) to give 6.62 g (13.7 mmol) of theabove-titled compound.

¹H-NMR δ (CDCl₃):0.68 (3H, d, J=6.6 Hz), 1.03 (3H, d, J=6.6 Hz), 2.31(1H, br), 3.44-3.54 (3H, m), 8.27 (1H, d, J=8.3 Hz), 13.14 (1H, br)

Reference Example 3 Preparation of4-isopropyl-3-(1-benzylpiperidin-4-yl)-3,4-dihydro-2(1H)-quinazolinone

Into a solution of 6.58 g (13.6 mmol) of1-benzyl-4-[2-methyl-1-(2-trichloroacetylaminophenyl)propylamino]piperidinein 136 ml of dimethylformamide, 9.42 g (68 mmol) of potassium carbonatewere added and stirred at 90° C. for 5 hours. The reaction mixture wascooled to room temperature, and then 0.5% aqueous potassium carbonatesolution and ethyl acetate-toluene (1:1) were added thereto and stirred.The separated oil layer was washed with saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theconcentrated residue was purified by silica gel column chromatography(chloroform/methanol 100/2) to give 3.65 g (10.0 mmol) of theabove-titled compound.

¹H-NMR δ (CDCl₃): 0.73 (3H, d, J=6.8 Hz), 0.89 (3H, d, J=7.0 Hz), 1.80(1H, m), 3.01 (2H, m), 4.25 (2H, s), 4.32 (1H, d, J=3.6 Hz), 6.97 (1H,d, J=7.0 Hz), 9.14 (1H, s), 9.95 (1H, br)

Reference Example 4 Preparation of4-isopropyl-3-(piperidin-4-yl)-3,4-dihydro-2(1H)-quinazolinone

Into a solution of 2.30 g (6.33 mmol) of4-isopropyl-3-(1-benzylpiperidin-4-yl)-3,4-dihydro-2(1H)-quinazolinonein 127 ml of methanol, 0.23 g (0.11 mmol) of 10% palladium carbon (50%wet) and 1.60 g (25.3 mmol) of ammonium formate were added and refluxedunder stirring and heating for 4 hours. After cooling to roomtemperature, the reaction mixture was filtered. To the filtrate, 0.5%aqueous sodium hydroxide solution and chloroform were added and stirred.The separated oil layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography(chloroform/methanol/triethylamine 90/10/5) to give 1.73 g (6.33 mmol)of the above-titled compound.

¹H-NMR δ (CDCl₃): 0.75 (3H, d, J=6.9 Hz), 0.90 (3H, d, J=6.9 Hz),1.62-1.66 (1H, m), 4.12 (1H, m), 4.30 (1H, d, J=3.9 Hz), 6.73 (1H, d,J=7.7 Hz), 7.54 (1H, s)

Test Example

Effect on Rhythmic Contractions of Bladder

This test was carried out by some modification of the method of Hedge etal. [Hedge S S. Choppin A. Bonhaus D. Briaud S. Loeb M. Moy T M. LouryD. Eglen R M., British Journal of Pharmacology. 120(8):1409-18, 1997].Female SD-rats were subjected to abdominal midline incision underurethane anesthesia (0.6 g/kg, s.c. and i.p.), the ureters were ligated,and its kidney side was cut off. A polyethylene cannula was insertedfrom the urethra into the bladder and the urethra was ligated. The otherend of the cannula was connected to a three way connector, to which aconstant infusion pump having a 20 ml attached syringe and a pressuretransducer for cystometry were also connected. A cannula foradministration of a test sample was inserted into the jugular vein and acannula for measurement of blood pressure and heart rate was insertedinto the carotid artery. The intravesical pressure, blood pressure andheart rate were continuously recorded on a polygraph. Physiologicalsaline was infused until rhythmic contractions of the bladder wereobserved, and after having confirmed stable rhythmic contractions of thebladder, vehicle (10% PEG) and solutions of a test sample dissolved in10% PEG were administered intravenously in turn from its lower dose. Themean of amplitude and frequency of bladder contraction during a10-minute period after administration were measured at each dose level,and their rates of change relative to the values obtained when thevehicle alone was administered were calculated, thereby determining ED₃₀values for the contractile amplitude and the contractile frequency,respectively. The results are shown in Table 1. It is apparent fromTable 1 that the compounds of the present invention depressed not onlythe contractile amplitude but also the contractile frequency.

TABLE 1 Contractile amplitude: Contractile frequency: Example Nos. ED₃₀(mg/kg) ED₃₀ (mg/kg) 1 (Hydrochloride) 1.71 1.31 2-1 (Hydrochloride)1.09 0.70 2-3 (Hydrochloride) 1.10 1.54 2-4 (Hydrochloride) 1.42 1.35 3(Hydrochloride) 0.94 1.79

INDUSTRIAL APPLICABILITY

The compounds of the present invention have not only a selectiveantagonism for the M3 muscarinic receptor but also a depressant actionon the frequency of rhythmic bladder contractions, and they are usefulfor the treatment of pollakiuria and urinary incontinence.

1. An optically active (+) form of the quinazolinone derivativesrepresented by the general formula (1):

wherein Y represents a C2-C7 alkyl group; E represents a nitrogen atom;and R represents a fluorine atom, C1-C4 alkyl group, C1-C4 alkoxy group,trifluoromethoxy group or 2,2,2-trifluoroethoxy group, orpharmaceutically acceptable salt thereof.
 2. The optically active formof the quinazolinone derivatives described in claim 1, wherein Y is aC3-C7 alkyl group, or pharmaceutically acceptable salt thereof. 3.(+)-3-{1-[3-(2,2,2-trifluoroethoxy)benzyl]piperidin-4-yl}-4-phenyl-3,4dihydro-2(1H)-quinazolinoneor pharmaceutically acceptable salt thereof. 4.(+)-3-[1-(3-trifluoromethoxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinoneor pharmaceutically acceptable salt thereof. 5.(+)-4-isopropyl-3-{1-[(6-methyl-2-pyridinyl)methyl]piperidin-4-yl}-3,4dihydro-2(1H)-quinazolinoneor pharmaceutically acceptable salt thereof. 6.(+)-3-[1-(3-trifluoromethoxybenzyl)piperidin-4-yl]-4-phenyl-3,4dihydro-2(1H)-quinazolinonefumarate.
 7. A medicament comprising the compound described in any ofclaims 1 or 3-6 or pharmaceutically acceptable salt thereof.
 8. A methodfor treating pollakiuria or urinary incontinence which comprisesadministrating an effective amount of the compound described in any ofclaims 1 or 3-6 or pharmaceutically acceptable salt thereof to a patientin need.
 9. A medicament comprising the optically active form of thequinazolinone derivatives described in claim 1, wherein Y is C3-C7 alkylgroup, or pharmaceutically acceptable salt thereof.
 10. A medicamentcomprising the optically active form of the quinazolinone derivativesdescribed in claim 1, wherein Y is C3-C7 alkyl group, orpharmaceutically acceptable salt thereof.
 11. A method for treatingpollakiuria or urinary incontinence which comprises administrating aneffective amount of the optically active derivatives described in claim1, wherein Y is C3-C7 alkyl group, or pharmaceutically acceptable saltthereof to a patient in need.
 12. A method for treating pollakiuria orurinary incontinence which comprises administrating an effective amountof the optically active derivatives described in claim 1, wherein Y isC3-07 alkyl group, or pharmaceutically acceptable salt thereof to apatient in need.